The discovery of a genetic variant that is relatively common among people of Polynesian ancestry, but incredibly rare in most other populations, is giving scientists new clues about the genetic basis of high cholesterol in people of all ethnicities. The research, headed by University of Pittsburgh School of Public Health geneticists in partnership with several other groups, including the University of Otago and the Samoan health research community, linked a stop-gain variant of a gene BTNL9, with lower HDL-C and higher triglyceride concentrations across several independent cohorts of Polynesian individuals. The team says their findings demonstrate the importance of ensuring diversity in genetic databases.

“If we had only been looking in populations with European ancestry, we might have missed this finding entirely,” said Jenna Carlson, PhD, assistant professor of human genetics and biostatistics at Pitt Public Health. “It was through the generosity of thousands of Polynesian people that we were able to find this variant, which is a smoking gun that will spark new research into the biology underlying cholesterol.”

Carlson and colleagues reported on their findings in Human Genetics and Genomics Advances, in a paper titled, “A stop-gain variant in BTNL9 is associated with atherogenic lipid profiles,” in which they concluded, “This work highlights the importance of measuring association in non-European populations as it can provide insight not only into population-specific findings and benefits, but also to cross-population associations which may lead to therapeutic targets able to benefit multiple population groups.”

High cholesterol is a major cause of disease burden in countries of all income levels, is a risk factor for heart disease and stroke, and is estimated to cause 2.6 million deaths annually worldwide, according to World Health Organization figures cited by the researchers. “Atherogenic lipid profiles—increased total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) as well as decreased high-density lipoprotein cholesterol (HDLC)—are well-documented and heritable risk factors for cardiovascular disease (CVD) worldwide,” they wrote. And while changes in behavior, and drug treatments, have been successful in improving lipid profiles, CVD is still the leading cause of death worldwide, particularly among people of Polynesian and Pacific Island ancestry.

Genome-wide association studies (GWAS) have identified a number of genetic links to lipid profiles, adding to what scientists know and understand about cardiovascular disease and potential targets, the team continued. However, much of this research has come from studies in European-ancestry populations. “ … limited effort has focused on Polynesian populations, whose unique population history and high prevalence of dyslipidemia may provide insight into the biological foundations of variation in lipid levels.”

For their study, Carlson and colleagues focused on a finding from a large genome-wide survey looking for genes associated with lipids, or fats, in the body. This suggested that a region of chromosome 5, 5q35, could be associated with cholesterol. “One region of interest is 5q35, which has previously been associated with HDL-C levels in Micronesian and Samoan populations,” they wrote. The team set out to fine map this chromosome region using genetic data from 2,851 Samoan adults in the Obesity, Lifestyle, And Genetic Adaptations (OLAGA, which means “life” in Samoan) Study Group, for which health information, including lipid panels, was available.

Using data from these western Polynesian Samoan participants, the team was able to fill in the missing information around the region they were interested in on chromosome 5. This led them to the gene BTNL9, which produces a protein BTNL9, the precise role of which hasn’t yet been fully characterized.

The researchers found that Polynesian people with low levels of HDL, or “good” cholesterol, and high levels of triglycerides carried a stop-gain variant (rs200884524) in BTNL9, which meant that the gene was being directed to stop doing its protein-production job. This was a strong hint that the BTNL9 protein is involved in helping cells maintain healthy cholesterol levels.

When they looked for a similar association in another 3,276 Polynesian people from Samoa, American Samoa, and Aotearoa New Zealand, they found the same connection between the gene variant and cholesterol. The team noted, “Little is known about the function of BTNL9 and the mechanism by which it may impact serum lipids; however, it has been previously associated with cardiomyopathy, pre-eclampsia, and various cancers … “BTNL9 belongs to the butyrophilin (BTN) family of membrane proteins which is part of a superfamily of immunoglobulin (Ig) receptors. Several studies suggest a role of BTN proteins in inflammatory and immunological functions ….”

“We don’t know a lot about this variant because it’s not seen in published genome references, which overrepresent European ancestry individuals—it’s virtually nonexistent in European ancestry populations, has very low frequency in South Asians, and isn’t even particularly common in eastern Polynesian people, such as Māori living in Aotearoa New Zealand,” Carlson said. “But the way it’s linked to lipid panels in Samoan people tells us that this gene is important to cholesterol, something we didn’t know before. By further exploring BTNL9, we might someday discover new ways to help everyone maintain healthy cholesterol levels.”

Moreover, the authors noted, “While this variant appears to be Polynesian-specific, there is also evidence of association from other multi-ancestry analyses in this region ….” The team cites other research highlighting a potential association between a variant of a nearby gene, BTNL3, with HDL-C in individuals of European descent. Another multi-ancestry meta-analysis identified links between variants in a gene, BTNL8, and total and HDL cholesterol, the investigators pointed out. “Furthermore, there were significant associations between pLoF variants in BTNL9 and both apolipoprotein A and HDL-C observed in gene-based studies of European-ancestry individuals also from the UKBiobank.” they wrote. This variant is rare in the Samoan discovery cohort, they noted.

They pointed out that additional work will be needed to characterize the relationship between variation in BTNL9 and lipid levels, “ … especially analyzing the impact of the nearby deletion in BTNL8/BTNL3, as well as any potential interaction between immune cells and lipid transport pathways.” But in conclusion, the team wrote, “This work provides evidence of a previously unexplored contributor to the genetic architecture of lipid levels and underscores the importance of genetic analyses in understudied populations.”

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